Criteria for adoption of new therapies and treatment paradigms in community oncology practices can differ substantively from that of academic medical centers. Differences arise, in part, from the influence of patient mix, available resources and services offered, physician/staff experiences, and the adherence to uniform treatment guidelines. Georgia Cancer Specialists (GCS) is a 31-site community-based group practice with 41 hematologists/oncologists motivated to standardize medical decision-making and optimize patient outcomes and health-care resource utilization.
Using our integrated electronic medical records and billing database (OASIS), we conducted a retrospective evaluation to assess the impact of 3 new agents (decitabine, 5-azacitidine, and lenalidomide) on practice patterns and outcomes in an elderly population with myelodysplastic syndrome (MDS) in the community setting. From January 2006 to June 2007, data from 1161 patients with MDS (mean age, 71 years; 63% women; 60% Medicare/Medicaid recipients) were collected. Of these, 76 patients (6.5%) received ≥ 1 MDS-indicated therapeutic agent (47% decitabine, 32% 5-azacitidine, 46% lenalidomide; 25% received ≥ 2 agents) for a median of 3, 2, and 3 cycles, respectively.
In general, the data suggest that patients receiving MDS-therapeutic agents had hematologic improvement and experienced reductions in transfusion requirements. The GCS population and treatment-related data reflect the uptake of new MDS therapeutic agents introduced proactively into a real-world community oncology practice and supplements information from randomized clinical trials.
Data derived from the community setting have the potential to provide important insights about actual disease prevalence, patient demographics, factors that influence medical careseeking, clinical management, and outcomes outside of academic institutions.
The risk of recurrent venous thromboembolism (VTE) in patients with polycythemia vera and essential thrombocythemia has been scarcely addressed, and whether long-term oral anticoagulant treatment or acetylsalicylic acid should be recommended after first occurrence of deep venous thrombosis (DVT) is unknown. This multicenter cohort study was aimed to assess the rate of recurrent VTE in patients with polycythemia vera or essential thrombocythemia in comparison with a control group of individuals with previous VTE and without neoplastic diseases.
We retrospectively estimated the rate of recurrence in 79 patients with myeloproliferative disorders (MPDs; polycythemia vera/essential thrombocythemia, 45/34) and with a previous proximal DVT. Patients were divided into 2 groups. The first comprised 41 patients who received acetylsalicylic acid after 6 months of oral anticoagulant treatment. The second group was composed of 38 patients given long-term oral anticoagulant treatment without acetylsalicylic acid. The majority of patients were treated with cytotoxic drugs. The results were compared with the recurrences seen in 176 patients without cancer with previous proximal DVT given short-term oral anticoagulant treatment.
In the patients with polycythemia vera and essential thrombocythemia, the rate of recurrent DVT was higher in the group receiving acetylsalicylic acid (32%) compared with the group on oral anticoagulant treatment (16%), although not statistically significant. The rate of recurrent DVT in MPD cases receiving acetylsalicylic acid was quite similar to that of patients without cancer (33%). The cumulative probability of recurrent VTE indicated a trend of fewer events in the MPD cases on long-term oral anticoagulant treatment. In the patients with MPDs, the incidence of major bleeding during oral anticoagulant treatment or acetylsalicylic acid was 1% and 0.5% patient-years (years of observation), respectively.
This retrospective analysis would suggest a long-term oral anticoagulant treatment after a first DVT in patients with polycythemia vera and essential thrombocythemia. However, this indication should be weighed against the risk of major hemorrhagic events that seems lower during long-term prophylaxis with acetylsalicylic acid. Therefore, a prospective clinical trial comparing acetylsalicylic acid in patients with polycythemia vera and essential thrombocythemia with oral anticoagulant treatment in the prevention of recurrent VTE is warranted.
Resistance to imatinib and second-generation tyrosine kinase inhibitors is an ongoing problem most frequently mediated through mutations of the Bcr-Abl kinase domain. One mutation that affects responsiveness to all current available agents is T315I. Aurora proteins belong to a small family of serine/threonine kinases that are essential for proliferating cells and have been identified as key regulators of different steps in mitosis and meiosis, ranging from the formation of the mitotic spindle up to cytokinesis. Unexpectedly, Aurora kinase inhibitors have been found to have activity against the T315I bcr-abl mutation, and some of them might rise as important therapeutic options. The common mechanism of action for protein kinase inhibition is competition with adenosine triphosphate for the active site-binding pocket, which is very similar among the protein kinases, and this could explain the cross-reactivity. Herein, we discuss the basics of imatinib resistance development and Aurora kinase biology, and describe a selected group of Aurora kinase inhibitors with potential activity in this patient population.
The application of sophisticated technologies in the diagnosis of hematologic malignancies has accelerated our knowledge about the molecular basis of the disease, and at present, much more is known about leukemia than any other type of cancer. Advances in our understanding of the pathogenesis of the disease offer exciting prospects. It was recognized that genetic alterations can be detected at diagnosis in the majority of patients with hematologic malignancies. Most important, increased application of these technologies in the clinical setting might lead to identification of relevant pathways for the design of novel therapies with the potential to change the medicine fundamentally.
The introduction of new therapeutic strategies has resulted in increased complete remission rates in B-cell chronic lymphocytic leukemia (CLL). Preliminary data have suggested that the absence of minimal residual disease (MRD) is an endpoint of therapy that, if achieved, translates into an improved survival. We developed and validated a novel, combined method to assess MRD in CLL using fluorescence-activating cell sorting (FACS) and interphase fluorescence in situ hybridization (FISH) for the detection of numeric chromosomal aberrations.
Cell sorting was performed on a FACS-Aria based on the CD19+CD5+ co-expression. Interphase FISH analysis was applied to purified cells with commercially available probes (Vysis/Abbott). Spiking experiments of CLL cells harboring a numeric chromosomal abnormality into normal blood with dilutions of 10−3 to 10−6 were performed; FISH detection of the specific chromosomal aberration in CD19+CD5+ purified cells allowed discrimination of CLL cells from normal precursor B-cells.
Positive results were demonstrated in all dilutions up to 10−5 or even 10−6. This approach for the assessment of MRD in CLL reaches sensitivity at least as high as and even higher than other methods, such as 4-color flow cytometry or quantitative allele-specific polymerase chain reaction.
It can be used for ≥ 80% of patients with CLL, including all patients with CLL with poor prognosis, as assessed by the presence of the deletion 11q (ataxia telangiectasia-mutated) or the deletion 17p (p53). Furthermore, it allows easy standardization among laboratories that apply FACS because it is based on 2-color labeling only and on FISH assays using commercially available probes.
Whereas chronic lymphocytic leukemia (CLL) responds to therapy, patients invariably experience relapse, and many patients with advanced disease acquire mutation or deletion of the p53 gene, resulting in resistance to most standard therapies. Alemtuzumab is active against p53-deficient CLL but is ineffective against bulky nodal disease and causes significant immunosuppression. Therefore, new therapies for patients with high-risk, relapsed CLL are needed. The synthetic flavone flavopiridol induces apoptosis of CLL cells in vitro, but clinical trials administering flavopiridol by 24–72–hour continuous intravenous (I.V.) infusion observed no clinical activity. Binding to human plasma proteins resulted in inadequate free flavopiridol concentrations with continuous I.V. infusion dosing schedules. Pharmacokinetic modeling indicated that administering flavopiridol by 30-minute I.V. bolus followed by 4-hour continuous I.V. infusion would achieve serum concentrations necessary to induce in vitro apoptosis. A phase I study demonstrated the clinical activity of this novel dosing regimen of flavopiridol in patients with relapsed, genetically high-risk CLL. The dose-limiting toxicity was acute tumor lysis syndrome, which resulted in fatal hyperkalemia in 1 patient. However, flavopiridol can be given safely with close monitoring and aggressive intervention for hyperkalemia, including hemodialysis if necessary. Nineteen of the first 42 patients in the phase I study had a partial response (45%), including 5 of 12 patients (42%) with del(17p13) and 13 of 18 patients (72%) with del(11q22). Ongoing phase II studies are studying modifications to optimize the dose and schedule of administration and to minimize treatment-related toxicities such as transient neutropenia and cytokine release syndrome. Flavopiridol is also being studied in acute leukemias, lymphomas, and solid malignancies.
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